| 1. |
- Albinsson, Sebastian, et al.
(författare)
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Arterial remodeling and plasma volume expansion in caveolin-1 deficient mice.
- 2007
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Ingår i: American Journal of Physiology: Regulatory, Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 293, s. 1222-1231
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Tidskriftsartikel (refereegranskat)abstract
- Caveolin- 1 ( Cav- 1) is essential for the morphology of membrane caveolae and exerts a negative influence on a number of signaling systems, including nitric oxide ( NO) production and activity of the MAP kinase cascade. In the vascular system, ablation of caveolin- 1 may thus be expected to cause arterial dilatation and increased vessel wall mass ( remodeling). This was tested in Cav- 1 knockout ( KO) mice by a detailed morphometric and functional analysis of mesenteric resistance arteries, shown to lack caveolae. Quantitative morphometry revealed increased media thickness and media- to- lumen ratio in KO. Pressure- induced myogenic tone and flow- induced dilatation were decreased in KO arteries, but both were increased toward wild- type ( WT) levels following NO synthase ( NOS) inhibition. Isometric force recordings following NOS inhibition showed rightward shifts of passive and active length- force relationships in KO, and the force response to alpha 1- adrenergic stimulation was increased. In contrast, media thickness and force response of the aorta were unaltered in KO vs. WT, whereas lumen diameter was increased. Mean arterial blood pressure during isoflurane anesthesia was not different in KO vs. WT, but greater fluctuation in blood pressure over time was noted. Following NOS inhibition, fluctuations disappeared and pressure increased twice as much in KO ( 38 +/- 6%) compared with WT ( 17 +/- 3%). Tracer- dilution experiments showed increased plasma volume in KO. We conclude that NO affects blood pressure more in Cav- 1 KO than in WT mice and that restructuring of resistance vessels and an increased responsiveness to adrenergic stimulation compensate for a decreased tone in Cav- 1 KO mice.
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| 2. |
- Tofik, Rafid, et al.
(författare)
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Increased urine IgM excretion predicts cardiovascular events in patients with type 1 diabetes nephropathy.
- 2009
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 7:Aug 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Diabetic nephropathy, a major complication of diabetes, is characterized by progressive renal injury and increased cardiovascular mortality. An increased urinary albumin excretion due dysfunction of the glomerular barrier is an early sign of diabetic nephropathy. An increased urinary excretion of higher molecular weight proteins such as IgM appears with progression of glomerular injury. We aim here to study the prognostic significance of urine IgM excretion in patients with type 1 diabetes mellitus (type 1 diabetic nephropathy). METHODS: This is an observational study of 139 patients with type 1 diabetes mellitus (79 males and 60 females) under routine care at the diabetic outpatient clinic at the Lund University Hospital. The median follow-up time was 18 years (1 to 22) years. Urine albumin and urine IgM concentration were measured at time of recruitment. RESULTS: Overall 32 (14 male and 18 female) patients died in a cardiovascular event and 20 (11 male and 9 female) patients reached end-stage renal disease. Univariate analysis indicated that patient survival and renal survival were inversely associated with urine albumin excretion (RR = 2.9 and 5.8, respectively) and urine IgM excretion (RR = 4.6 and 5.7, respectively). Stratified analysis demonstrated that in patients with different degrees of albuminuria, the cardiovascular mortality rate and the incidence of end-stage renal disease was approximately three times higher in patients with increased urine IgM excretion. CONCLUSION: An increase in urinary IgM excretion in patients with type 1 diabetes is associated with an increased risk for cardiovascular mortality and renal failure, regardless of the degree of albuminuria.
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| 3. |
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| 4. |
- Rippe, Bengt, et al.
(författare)
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Long-term clinical effects of a peritoneal dialysis fluid with less glucose degradation products
- 2001
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Ingår i: Kidney Int. - : Elsevier BV. ; 59:1, s. 348-357
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Glucose degradation products (GDPs) are cytotoxic in vitro and potentially toxic in vivo during peritoneal dialysis (PD). We are presenting the results of a two-year randomized clinical trial of a new PD fluid, produced in a two-compartment bag and designed to minimize heat-induced glucose degradation while producing a near neutral pH. The effects of the new fluid over two years of treatment on membrane transport characteristics, ultrafiltration (UF) capacity, and effluent markers of peritoneal membrane integrity were investigated and compared with those obtained during treatment with a standard solution. DESIGN: A two-group parallel design with 80 continuous ambulatory peritoneal dialysis patients was used. The patients were randomly assigned to either the new fluid (N = 40) or to a conventional one (N = 40), and were stratified with respect to age, diabetes, and time on PD. Peritoneal transport characteristics were assessed by the Personal Dialysis Capacity (PDCtrade mark) test at 1, 6, 12, 18, and 24 months after inclusion and by weighing the overnight bag daily. Infusion pain and handling were evaluated using a questionnaire. Peritoneal mesothelial and interstitial integrity were evaluated by analyzing overnight effluent dialysate concentrations of CA 125, hyaluronan (HA), procollagen-1-C-terminal peptide (PICP), and procollagen-3-N-terminal peptide (PIIINP) at 1, 6, 12, 18, and 24 months. RESULTS: The handling of the new two-compartment bag was considered easy, and there were no indications of increased discomfort with the new system. Furthermore, no changes in peritoneal fluid or solute transport characteristics were observed during the study period for either fluid, and neither were there any differences with regard to peritonitis incidence. However, significantly higher dialysate CA 125 (73 +/- 41 vs. 25 +/- 18 U/mL), PICP (387 +/- 163 vs. 244 +/- 81 ng/mL), and PIIINP (50 +/- 24 vs. 29 +/- 13 ng/mL) and significantly lower concentrations of HA (395 +/- 185 vs. 530 +/- 298 ng/mL) were observed in the overnight effluent during treatment with the new fluid. CONCLUSIONS: We conclude that the new fluid with a higher pH and less GDPs is safe and easy to use and has no negative effects on either the frequency of peritonitis or peritoneal transport characteristics as compared with conventional ones. Our results indicate that the new solution causes less mesothelial and interstitial damage than conventional ones; that is, it may be considered more biocompatible than a number of conventional PD solutions currently in use.
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| 5. |
- Rippe, Catarina, et al.
(författare)
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Nature of glomerular capillary permeability changes following acute renal ischemia/reperfusion (I/R) injury in rats.
- 2006
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 291:6, s. 1362-1368
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Tidskriftsartikel (refereegranskat)abstract
- This study was performed to evaluate the alterations of glomerular filtration barrier characteristics following acute renal ischemia-reperfusion (I/R). Ischemia was induced in anesthetized rats by unilateral renal artery occlusion for either 20 or 60 min, followed by reperfusion during 20 or 60 min, respectively, with the contralateral kidney serving as control. Sieving coefficients (theta) were obtained by analyzing Ficoll [mol.radius (a(e)) 13-85 angstrom] in urine and plasma after 20 and 60 min I/R. Furthermore, theta for human serum albumin (HSA) was estimated using a tissue uptake technique after 20 and 60 min of I/R, while clearance of HSA compared with that for neutralized HSA (nHSA) was assessed after 20 min of I/R only. Glomerular filtration rate (GFR) was measured by [Cr-51] EDTA and inulin. I/R reduced GFR and increased theta for Ficoll molecules of a(e) > 55 angstrom and theta for albumin. theta for Ficoll vs. a(e), analysed using a two-pore model, demonstrated that, despite increases in theta, the large-pore fractional ultrafiltration coefficient (alpha(L)) was unchanged after 20 min of I/R, owing to the decline in GFR, but increased after 60 min of I/R. However, the apparent alpha(L) for albumin increased already after 20 min of I/R (P < 0.005) and the nHSA/HSA clearance ratio was slightly reduced, possibly reflecting a diminished negative charge barrier. In conclusion, after 20 min of I/R, indications of a reduced charge selectivity were noted, while after 60 min of I/R, there was mainly a reduction in size selectivity, compatible with an increased formation of large pores.
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| 6. |
- Sverrisson, Kristinn, et al.
(författare)
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Extracellular fetal hemoglobin induces increases in glomerular permeability: inhibition with alfa-1-microglobulin and tempol
- 2014
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Ingår i: American Journal of Physiology-Renal Physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 306:4, s. 442-448
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular fetal hemoglobin (HbF) and adult hemoglobin (HbA) are proinflammatory and generate ROS. Increased plasma levels of extracellular HbF have recently been reported to occur in early preeclampsia. α1-Microglobulin (A1M) is a physiological heme-binding protein and radical scavenger that has been shown to counteract vascular permeability increases induced by HbA in the perfused placenta. The present study was performed to investigate whether HbF and HbA will increase glomerular permeability in vivo and to test whether A1M and tempol, a ROS scavenger, can prevent their effects. Anesthetized Wistar rats were continuously infused intravenously with either HbA, HbF, or cyano-inactivated HbF together with FITC-Ficoll-70/400, inulin, and51Cr-labeled EDTA for 2 h. Plasma samples and urine samples (left ureter) were taken repeatedly and analyzed by high-performance size exclusion chromatography to assess glomerular sieving coefficients for Ficoll of radius 10–80 Å. In separate experiments, A1M or tempol was given before and during Hb infusions. Extracellular HbF caused rapid, transient increases in glomerular permeability to large Ficoll molecules (50–80Å), contrary to the effects of HbA and cyano-inactivated HbF. For HbF, glomerular sieving coefficients for Ficoll of radius 60Å increased from 3.85 ± 0.85 × 10−5to 2.60 ± 0.96 × 10−4at 15 min, changes that were abrogated by tempol and reduced by A1M. In conclusion, our data demonstrate that extracellular HbF, infused systemically, can acutely increase glomerular permeability through inducing oxidative stress.
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| 7. |
- Wester Rosenlöf, Lena, et al.
(författare)
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A1M/α1-Microglobulin Protects from Heme-Induced Placental and Renal Damage in a Pregnant Sheep Model of Preeclampsia.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Preeclampsia (PE) is a serious pregnancy complication that manifests as hypertension and proteinuria after the 20(th) gestation week. Previously, fetal hemoglobin (HbF) has been identified as a plausible causative factor. Cell-free Hb and its degradation products are known to cause oxidative stress and tissue damage, typical of the PE placenta. A1M (α1-microglobulin) is an endogenous scavenger of radicals and heme. Here, the usefulness of A1M as a treatment for PE is investigated in the pregnant ewe PE model, in which starvation induces PE symptoms via hemolysis. Eleven ewes, in late pregnancy, were starved for 36 hours and then treated with A1M (n = 5) or placebo (n = 6) injections. After injections, the ewes were re-fed and observed for additional 72 hours. They were monitored for blood pressure, proteinuria, blood cell distribution and clinical and inflammation markers in plasma. Before termination, the utero-placental circulation was analyzed with Doppler velocimetry and the kidney glomerular function was analyzed by Ficoll sieving. At termination, blood, kidney and placenta samples were collected and analyzed for changes in gene expression and tissue structure. The starvation resulted in increased amounts of the hemolysis marker bilirubin in the blood, structural damages to the placenta and kidneys and an increased glomerular sieving coefficient indicating a defect filtration barrier. Treatment with A1M ameliorated these changes without signs of side-effects. In conclusion, A1M displayed positive therapeutic effects in the ewe starvation PE model, and was well tolerated. Therefore, we suggest A1M as a plausible treatment for PE in humans.
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| 8. |
- Lund, Ulla, et al.
(författare)
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Glomerular filtration rate dependence of sieving of albumin and some neutral proteins in rat kidneys
- 2003
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 284:6, s. 1226-1234
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Tidskriftsartikel (refereegranskat)abstract
- The size and charge-selective properties of the glomerular barrier are partly controversial. Glomerular sieving coefficients (theta) for proteins have rarely been determined noninvasively before in vivo. Therefore, theta was assessed vs. glomerular filtration rate (GFR; Cr-51-EDTA clearance) in intact rats for radiolabeled myoglobin, kappa-dimer, neutral horseradish peroxidase (nHRP), neutral human serum albumin (nHSA), and native albumin (HSA). To obtain theta, glomerular tracer clearance, assessed from the 7- to 8-min kidney uptake of protein, was divided by the GFR. The data were fitted with a two-pore model of glomerular permeability, where the small-pore radius was 37.35 +/- 1.11(SE) Angstrom, and the "unrestricted pore area over diffusion path length" (A(0)/DeltaX) 1.84 +/- 0.43 . 10(6) cm. Although seemingly horizontal for nHRP and nHSA, the log theta vs. GFR curves showed slightly negative slopes for the proteins investigated in the GFR interval of 2-4.5 ml/min. Strong negative ( linear) correlations between ( log) theta and GFR were obtained for myoglobin (P = 0.002) and HSA (P = 0.006), whereas they were relatively weak for nHRP and nHSA and nonsignificant for kappa-dimer. theta for nHSA was markedly higher than that for HSA. In conclusion, there were no indications of increases in theta vs. GFR, as indicative of concentration polarization, for the proteins investigated at high GFRs. Furthermore, the glomerular small-pore radius assessed from endogenous (neutral) protein sieving data was found to be smaller than previously determined using dextran or Ficoll as test molecules.
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| 9. |
- Grände, Gustaf, et al.
(författare)
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Unaltered Size-selectivity of the Glomerular Filtration Barrier in Caveolin-1 Knock-out (KO) mice.
- 2009
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Ingår i: American Journal of Physiology: Renal, Fluid and Electrolyte Physiology. - : American Physiological Society. - 0363-6127. ; 297:2, s. 257-262
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Tidskriftsartikel (refereegranskat)abstract
- The transfer of albumin from blood to tissue has been found to be increased in caveolin-1 knock-out (KO) mice. This has been considered to reflect an increased microvascular permeability, conceivably caused by an increased endothelial production of nitric oxide (NO) in mice lacking caveolin-1. To investigate whether such an increase in endothelial NO-production would also affect the glomerular barrier characteristics, the glomerular sieving coefficients () to neutral, polydisperse fluorescein isothiocyanate (FITC)-Ficoll 70/400 (mol. radius 15-90 A) were determined in caveolin-1 KO mice vs. their wild-type counterparts. for Ficoll were assessed using high performance size exclusion chromatography (HPSEC) on blood and urine samples. Furthermore, the transcapillary escape rate (TER) of (125)I-labeled albumin and plasma volume (PV) were determined in both types of mice. Despite an increase in the glomerular filtration rate (GFR) in caveolin-1 KO mice (0.23+/-0.04 mL/min; n=7 vs. 0.10+/-0.02 mL/min; n=7; p<0.05) the glomerular Ficoll sieving curves were nearly identical. Furthermore, caveolin-1 KO mice showed an increased PV (6.59+/-0.42 mL/100g vs. 5.18+/-0.13 mL/100g; p<0.01) but only a tendency of an increased TER (14.69+/-1.59 %/h vs. 11.62+/-1.62 %/h; N.S.). It is concluded that in caveolin-1 KO mice the glomerular permeability was not increased, despite the presence of glomerular hyperfiltration. The present data are in line with the concept that the increased transvascular albumin leakage previously found in mice lacking caveolin-1 may be due to an elevation in systemic microvascular pressure following NO-induced precapillary vasodilatation, rather than being a consequence of an increased microvascular permeability per se. Key words: capillary permeability, nitric oxide, sieving coefficient, Ficoll, glomerular filtration rate.
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| 10. |
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